Huntington's Disease (HD) is a neurological disorder resulting from CAG triplet repeat genetic mutation of the IT15 gene that encodes the huntingtin protein. Extensive data in the field indicate that proteolytic fragment(s) of htt mediate the HD disease process, resulting in severe motor disturbances. The goal of this project will be to discover novel marine natural product compounds as potential therapeutic agents for Huntington's disease (HD). This project fulfills a major gap in the HD and neurodegenerative disease field for discovery of novel agents as protease inhibitors for future development of therapeutic agents for HD. Furthermore, this project uses novel marine natural products as a unique opportunity for drug discovery in the protease target area to reduce production of neurotoxic htt proteolytic fragments that participate in HD. This unique project will integrate expertise in protease biochemistry and neurobiology by Dr. Vivian Hook, marine natural products for discovery of therapeutic agents by Dr. William Gerwick, and model striatal neuronal cells, as well as transgenic mice, expressing mutant huntingtin (htt) protein of Huntington's disease by Dr. Albert La Spada at the Univ. of Calif., San Diego. The project plan will implement interdisciplinary efforts of three highly experienced laboratories in the required disciplines to discover novel protease inhibitors of huntingtin protein proteolysis as a means to reduce cellular mutant htt neurotoxicity. This project can progress at a rapid pace since the collaborating laboratories have the required expertise, and are located in close proximity to one another at UC San Diego. HD drug discovery of this project will be accomplished in two specific aims. The first aim will evaluate marine natural product compounds for inhibition of protease activities thought to be involved in HD, which includes caspase, calpain, lysosomal proteases (cathepsins L, B, and D), and matrix metalloprotease 10. Cyanobacteria algal marine natural product compounds are a rich source of potent drug molecules with unique structural diversity. In aim 2, cyanobacterial marine natural compounds will be tested in cellular assays for reduction of N-terminal htt fragments and protection from cell death, using striatal-like neuronal cells that express full-length mutant huntingtin (htt) protein, and in control cells expressing normal htt protein. Effective compounds identified from aims 1 and 2 will be prioritized by their inhibitory potencies. These compounds will be planned for a future R01 project that will conduct in vivo testing of compounds in HD mouse models for effectiveness to improve the motor impairment in HD transgenic mice. Results can indicate candidate marine natural drug compounds for HD drug development.